Heterocyclic amino alcohols



2,712,022 Patented June 28, 1955 corresponding substituted aminopropenes by treatment 2 712 022 with an agent to remove the elements of water in the following manner HETEROCYCLIC AMINO ALCOHOLS OH Donaid Wallace Adamson, London, England, assignor to \Q:(}H2 CH2N=R2 Dewion Burroughs Wellcome & C0. (U. S. A.), Iuc., Tuckahoe, N. Y., a corporation of New York No Drawing. Application July 16, 1949, 1

Serial No. 105,257 \CZCH OH2N=R Claims priority, application Great Britain July 20, 1948 9 Claims. (Cl. 260-296) Q wherein R and R have the above mentioned values.

The conversion of the carbinol to the unsaturated amine may be effected by a variety of agents. It has been found satisfactory to add thionyl chloride to the carbinol disunsatllrai d and Saturated aminesy of these solved in an inert solvent such as benzene or chloroform rivativ s ar found to have Outstanding medicinal p p and then to boil the mixture under reflux on the steamerties in veterinary and human medicine, while others are 2'. b h f t h The solvent and excess thionyl chlouseflll intermediaries in the Prfiparation of related ride are removed by evaporation, the residue dissolved in pounds. water, excess of an alkali, such as ammonia, added and According to the present invention the new derivatives y be rePreseflted y the formula such as ether or chloroform. The base may be recovered 1 03 J by evaporation of the solvent and is purified by distilla-- \Q/OmombI==Ra tion under reduced pressure, or, if the base is a solid, by recrystallization from a su1table solvent. Alterna- Q tively the carbinol may be dehydrated by warming with concentrated sulphuric acid of strength 80% by weight wherein R denotes a radical selected from the class conapproximately fouawsd Dy basificafion and ixtractiml sisting of the phenyl thienyl, p chlomphenyl and as described above. The unsaturated amines so obtained oxyphenyl radicals a NR2 is a radical Selected from may be converted to their crystalline, water-soluble salts, the class consisting of the dimethyl, diethyl, piperidino i ti f g l f and pyrrolidino radicals and are prepared by bringing n an accor mg mvfintmn the unsaturated about a react on between an aminoethyl ketone of the amines of the above fgrmula in which R1 and R2 have the formula same meaning as above except that R must not be 2- RICOCHZCHZNzRZ thienyl, may if desired be reduced to the corresponding saturated amines of the formula wherein R and R have the above mentioned values with R1 the appropriate pyridyl lithium reagent and thereafter hydrolyzing the organo-lithium compound so produced. CHCHQCH2N=W The reaction is preferably carried out according to the \T invention by forming a solution or suspension of the organo-lithium compound in an inert solvent, usually ether, and bringing this into reaction with the aminoethyl A ketone by mixing the reactants together in an inert atmosphere and stirring for a short period preferably while The present invention relates to the preparation of novel aryl substituted tertiary aminocarbinols and to the dehydration of these derivatives to the corresponding The reduction is carried out by agitating a solution of a salt, such as the hydrochloride of the unsaturated amine in, for example, ethanol or aqueous ethanol in the cooling. The organo-lithium complex so formed is de- 5 z E s Such as Panadized carcoat in an a rnosp ere o y rogen at room tempera composed by the addition of water followed by an acid o ture or at elevated temperatw'es, at atmos' heric ressure Sucn aceuv or hydrochlo: 1c aclsi' The aqueous or at higher pressures. The product is isd lated ti y fi te layar 1S i' i madv i i the prod" ing off the catalyst evaporation of the solv nt and re uct extracte y a so vent suc as c oro orm. 1 1

or sallizatlon of the residual salt, or b ba ifi 1 r-emqvmg the Solvent the product 15 purified fr iciional distillation of the resulting ase by eistillation under reduced pressure or by crystatlizaridvn 1 1 b 7 tion and may be converted, if desired, nto water soluble J l gl ti O l y b6 v rt d by used in t e a ove escri e reaction are 'nown corn- H i e Pounds.f ghei) new derivatives rrliag l be lllseg eithfer inhthe g i i ggtggf i $1 313 3;; z gfs li gg $21120 formo te aseorawatersou esattereo suc as e r the hydrochloride The nonqoxic acid used to form the 60 thereby eliminating the intermediate formation of aminosalt is immaterial insofar as the physioflogical activity of P iE P p pa ed according to this V t the substance is concerned and is not 0 a critical nature. g In 10!! a a; 22st: stints?attract; rettiest; phoric acid or certain organic an s suc as ma 1c acu, e

i thera 11 succinic acid, lactic acid or the like may be employed and U nd 512355 333; 252 f $223238; diThtedarillnnoptroptilenes any of these may ofier advantagesm 1nd1v1dual cases, V In b1 t n Ca e c arac er aVB All non-toxic acids are considered to be equivalent for this g fi 'g i i i f purpose and all salts thereof are comprehended within g6 amp es Serve strate the lnventlonthe invention.

In accordance with another phase of the present invention the substituted l-(2-pyridyl)-1-arylpropan-1-ols prepared in the foregoing manner are converted into the Example 1 The following process was conducted in a flask fitted the liberated base separated by extraction with a solvent with a stirrer and a reflux condenser and provided with an inlet tube through which a slow stream of dry nitrogen was passed in order to maintain an inert atmosphere.

Lithium (12 g.) was added to l-chlorobutane (78 g.) dissolved in anhydrous other (250 millilitres) and the mixture boiled under reflux with stirring until the lithium had dissolved. The solution was then cooled to 40 C. and a solution of 2-bromopyridine (100 g.) in anhydrous ether (100 ml.) gradually added with stirring. After stirring for ten minutes at this temperature, 3-dimethylaminopropiophenone (35 g., freshly distilled; Mannich and Heilner, Berichte, 1922, volume 55, page 356) dissolved in ether (50 ml.) was gradually added and the mixture stirred at 15 C. for 3 hours. The product was then poured on to ice (200 g.) with stirring and acetic acid added until the mixture was acidic. The aqueous layer was then separated, shaken with ether, again separated, and excess ammonia added. The oil which separated was extracted with chloroform, the extract washed with water, dried over sodium sulphate and the chloroform evaporated. The residual oil which solidified on cooling furnished pure B-dimethylamino-l- (2'-pyridyl)-1-phenylpropan-1-ol (melting point 99- 100 C.), after recrystallization from light petroleum (boiling point 6080 C.). The oxalate, prepared by mixing ethanolic solutions of the base and of oxalic acid had melting point l51-153 C. (after being recrystallized from ethanol).

Example 2 Thionyl chloride (7.0 g.) in benzene (7 ml.) was added slowly to 3-dimethylamino-l-(2-pyridyl)-1-phenylpropan-l-ol (7.5 g.) dissolved in benzene (25 ml.) cooled in ice. The mixture was then boiled under reflux on the steam bath for 2 hours. Benzene and excess thionyl chloride were removed by evaporation under reduced pressure, and the residue dissolved in water. Excess ammonia was then added and the liberated base extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulphate and the chloroform evaporated. The residual oil on fractional distillation under reduced pressure, gave 3-dimethylamino-1-(2-pyridyl)-1-phenylprop-l-ene, a pale yellow oil, having boiling point 108 C./ 0.05 millimetres. The monohydrochloride of the base had melting point 181l82 C. (when recrystallized from a mixture of ethanol and ethyl acetate).

Example 3 3-dimethylamino-1-(2-pyridyl) -l-phenylprop-1-ene hydrochloride g.) dissolved in ethanol ml.) was shaken with palladized charcoal catalyst (2 g.) in an atmosphere of hydrogen. When absorption of hydrogen had ceased, the catalyst was filtered ofli, and the ethanol removed by evaporation. The residue was dissolved in water, excess of ammonia added, and the liberated base extracted by chloroform. The chloroform extract was dried by sodium sulphate, the chloroform removed by evaporation and the residual oil distilled under reduced pressure to give 3-dimethylamino-l-(2-pyridyl)-1-phenylpropane, a colorless liquid, boiling at 104106 C./0.05 mm. The neutral oxalate, prepared by mixing ethanolic solutions of the base and of oxalic acid, had melting point 154 C. (when recrystallized from ethanol).

Example 4 Lithium (2.2 g.) was added to l-chlorobutane (13.8 g.) dissolved in anhydrous ether (80 ml.) contained in a flask fitted with a stirrer, reflux condenser and inlet-tube through which a slow stream of dry notrogen was passed. The mixture was boiled under reflux with stirring until the lithium had dissolved. The solution was then cooled to. -40 C. and a solution of Z-bromopyridine (18 g.) in anhydrous ether ml.) gradually added with stirring. After stirring for ten minutes at C., 3-piperidino-p-chloropropiophenone hydrochloride (21.4 g.) was added in small portions. The temperature was then allowed to rise to -15 C. and stirring continued for 1 hour. The product was worked up by the method described in Example 1, yielding 3-piperidino-1-(2-pyridyl) l-p-chlorophenylpropan 1-01.

Example 5 Dehydration of 3-piperidino-l-(2'-pyridyl)-1-p-chlorophenylpropan-l-ol by the method described in Example 2 gave 3-piperidino-l-(2-pyridyl)-l-p-chlorophenylpropl-ene.

Example 6 Beta-dimethylamino -4- methoxypropiophenone, when treated with 2-pyridyl-lithium in a manner essentially similar to that described in Example 1, yielded B-dimethylamino-1-(4-methoxyphenyl) -1- (2-pyridyl)propan-1-ol, melting point 8990 C. (afterrecrystallization from ethanol). The dihydrochloride prepared therefrom melted with decomposition at 208-209 C. (after recrystallization from a mixture of methanol and ethyl acetate).

Example 7 Example 8 Beta-dimethylaminopropiothienone when treated with 2-pyridyllithium in a manner essentially similar to that described in Example 1, yielded 3-dimethylamino-1-(2'- pyridyl)-l-l(2-thienyl)propan1-ol, melting point 66- 67 C. (after recrystallization from light petroleum); the neutral oxalate melted with decomposition at 167 C. after recrystallization from a mixture of methanol and ethanol.

Example 9 3-dimethylamino-1-(2'-pyridyl) -1- (2'-thienyl)propanl-ol (5 g.) was added in portions to aqueous sulphuric acid (10 ml.) and the solution then heated in the steam bath for 10 minutes. The solution was cooled, diluted with water, basified and the product extracted with ether, and purified by distillation under reduced pressure. 3-dimethylamino-1-(2'-pyridyl) 1 (2'-thienyl)- prop-l-ene boiled at l16122 C./0.5 mm. and the neutral oxalate prepared therefrom melted at 161162 C. with decomposition.

Example 10 Beta diniethylamino parachloropropiophenone when reacted with 2-pyridyllithium in a manner essentially similar to that described in Example 1 yielded 3-dimethylamino l (4 chlorophenyl) I (2" pyridyl) propan-l-ol, melting point 8990 C. after recrystallization from ethanol.

The beta dimethylamino parachloropropiophenone (M. P. 58-59") was-prepared by the Mannich reaction from parachloroacetophenone, formaldehyde and dimethylamineythe hydrochloride melts at 174l75.

Example 1 I Dehydration of 3-dimethylaminol- 4'-chlorophenyl l-(2"-pyridyl)-propan-l-ol by the method described in Example 9 gave 3-dimethylamino-l-(4-chlorophenyl)-l- (2-pyridyl)-prop-l-ene which boiled at 1l8120 C./ 0.01 mm. The oxalate prepared therefrom melted with decomposition at 171 and the maleate at -166 with decomposition.

Example 12 Example 13 Dehydration of S-N-pyrrolidino-1-(4-chlorophenyl)- 1-(2"-pyridyl)propen-l-ol, by the method described in Example 9, gave 3 N pyrrolidino-1-(4'-chlorophenyl)- 1-(2"-pyridyl)-prop-1-ene which had a boiling point of 158160/0.01 mm. The oxalate prepared therefrom melted at 177 with decomposition.

Example 14 Treatment of the 3-N-pyrrolidino-1-(4-chlorophenyl)- 1-(2"-pyridyl)-prop-1-ene by the method of Example 3 yielded 3 N pyrrolidino 1 (4 chlorophenyl) 1 (2"-pyridyl)-propane.

Example 15 Following the procedure of Example 3, 3-piperidino-1- (2'-pyridyl)-1-p-chlorophenylprop-l-ene was reduced to 3-piperidino-1-(2'-pyridyl)-1-p-chlorophenylpropane.

Example 16 3 dimethylamino 1 (4 methoxyphenyl) 1 (2' pyridyD-prop-l-ene was treated by the procedure of Example 3 to give 3-dimethylamino-1-(4'-methoxyphenyl)- l-(2'-pyridyl)propane.

Example 17 The method of Example 1 was followed using 2-bromopyridine and 3-diethylamino-p-chloropropiophenone to yield 3 diethylamino 1 (2 pyridyl) 1 p chlorophenylpropan-l-ol.

Example 18 The compound of Example 17 was reduced by the method of Example 2 to form 3-diethylamino-1-(2'- pyridyl)-1-p-chlorophenylprop-l-ene.

Example 19 The allylamine of Example 18 was treated with palladized charcoal catalyst and hydrogen by the method of Example 3 to produce 3-diethylamino-l-(2'-pyridyl)- l-p-chlorophenylpropane.

I claim:

1. As a new compound a substance of the class consisting of the free base and non-toxic acid addition salts, said substance being represented by the formula R OH C OHaCHa :12

wherein R is a radical selected from the class consisting of phenyl, p-chlorophenyl and p-methoxyphenyl radicals and NR is a radical selected from the class consisting of the dimethylamino, diethylamino, pyrrolidino and piperidino radicals.

2. The method of making aminocarbinol compounds of the general formula o-omtunN wherein R is a radical selected from the class consisting of phenyl, p-chlorophenyl and p-methoxyphenyl radicals and NR is a radical selected from the class consisting of the dimethylamino, diethylamino, pyrrolidino and piperidino radicals, which process comprises reacting an aminoethyl ketone of the formula R COCH2CH2N R wherein R and R have the above mentioned values with Z-pyridyl lithium and hydrolyzing the organo-lithium compound so formed to liberate the aminocarbinol.

3. As a new compound 3-dimethylamino-1-(4'-chlorophenyl)-1-(2-pyridyl)-propan-l-ol.

4. As a new compound 3-N-pyrrolidino-l-(4'-chlorophenyl)-1-(2-pyridy1)-propan-1-ol.

5. As a new compound 3-diethylamino-1-(2'-pyridyl)- 1-p-chlorophenylpropan-l-ol.

6. A salt of 3-dimethylamino-1-(4'-chlorophenyl)-1- (2 -pyridyl)-propan-1-ol.

7. As a new compound a salt of 3-N-pyrrolidino-1- (4-chlorophenyl) l-(2"-pyridyl) -propan-1-ol.

8. As a new compound a substance of the class consisting of the free base and non-toxic acid addition salts, said substance being represented by the formula wherein R is a phenyl radical and NR is a radical selected from the class consisting of the dimethylamino, diethylamino, pyrrolidino and piperidino radicals.

9. The method of making aminocarbinol compounds of the general formula wherein R is a phenyl radical and NR is a radical selected from the class consisting of the dimethylamino, diethylamino, pyrrolidino and piperidino radicals, which process comprises reacting an aminoethyl ketone of the formula R COCHzCHzN=R wherein R and R have the above mentioned values with 2-pyridyl lithium and hydrolyzing the organolithium compound so formed to liberate the aminocarbinol.

References Cited in the file of this patent UNITED STATES PATENTS 1,978,539 Klarrer et al Oct. 30, 1934 1,980,638 Scheuing et al. Nov. 13, 1934 2,282,907 ter Horst May 12, 1942 2,344,814 Grun et al Mar. 21, 1944 2,411,664 Miescher et al Nov. 26, 1946 2,441,069 Hofiman et al. May 4, 1948 FOREIGN PATENTS 11,197 Great Britain of 1906' 240,363 Switzerland May 16, 1946 695,640 Germany Aug. 29, 1940 OTHER REFERENCES Burger et al., Jour. Amer. Chem. Soc., vol. 66 (1944), pp. 1327-28. 

1. AS A NEW COMPOUND A SUBSTANCE OF THE CLASS CONSISTING OF THE FREE BASE AND NON-TOXIC ACID ADDITION SALTS, SAID SUBSTANCE BEING REPRESENTED BY THE FORMULA
 2. THE METHOD OF MAKING AMINOCARBINOL COMPOUNDS OF THE GENERAL FORMULA 